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Emerging Complexity and the Need for Advanced Drug Delivery in Targeting Candida Species

Wadhwa R, Pandey P, Gupta G, Aggarwal T, Kumar N, Mehta M, et al.

Curr Top Med Chem, 2019;19(28):2593-2609.
PMID: 31746290 DOI: 10.2174/1568026619666191026105308

BACKGROUND: Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence system utilizes a wide array of the cells, proteins and chemical signals that are distributed in blood and tissues which further constitute the innate and adaptive immune system. The lack of antifungal agents and their limited therapeutic effects have led to high mortality and morbidity related to such infections.
METHODS: The necessary information collated on this review has been gathered from various literature published from 1995 to 2019.
RESULTS: This article sheds light on novel drug delivery approaches to target the immunological axis for several Candida species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. rugose, C. hemulonii, etc.).
CONCLUSION: It is clear that the novel drug delivery approaches include vaccines, adoptive transfer of primed immune cells, recombinant cytokines, therapeutic antibodies, and nanoparticles, which have immunomodulatory effects. Such advancements in targeting various underpinning mechanisms using the concept of novel drug delivery will provide a new dimension to the fungal infection clinic particularly due to Candida species with improved patient compliance and lesser side effects. This advancement in knowledge can also be extended to target various other similar microbial species and infections.
Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update

Mehta M, Dhanjal DS, Paudel KR, Singh B, Gupta G, Rajeshkumar S, et al.

Inflammopharmacology, 2020 Aug;28(4):795-817.
PMID: 32189104 DOI: 10.1007/s10787-020-00698-3

Respiratory disorders, especially non-communicable, chronic inflammatory diseases, are amongst the leading causes of mortality and morbidity worldwide. Respiratory diseases involve multiple pulmonary components, including airways and lungs that lead to their abnormal physiological functioning. Several signaling pathways have been reported to play an important role in the pathophysiology of respiratory diseases. These pathways, in addition, become the compounding factors contributing to the clinical outcomes in respiratory diseases. A range of signaling components such as Notch, Hedgehog, Wingless/Wnt, bone morphogenetic proteins, epidermal growth factor and fibroblast growth factor is primarily employed by these pathways in the eventual cascade of events. The different aberrations in such cell-signaling processes trigger the onset of respiratory diseases making the conventional therapeutic modalities ineffective. These challenges have prompted us to explore novel and effective approaches for the prevention and/or treatment of respiratory diseases. In this review, we have attempted to deliberate on the current literature describing the role of major cell signaling pathways in the pathogenesis of pulmonary diseases and discuss promising advances in the field of therapeutics that could lead to novel clinical therapies capable of preventing or reversing pulmonary vascular pathology in such patients.
Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression

Satija S, Kaur H, Tambuwala MM, Sharma P, Vyas M, Khurana N, et al.

Curr Mol Pharmacol, 2021;14(3):321-332.
PMID: 33494692 DOI: 10.2174/1874467214666210120154929

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.
Hydrogel composite containing azelaic acid and tea tree essential oil as a therapeutic strategy for Propionibacterium and testosterone-induced acne

Bisht A, Hemrajani C, Rathore C, Dhiman T, Rolta R, Upadhyay N, et al.

Drug Deliv Transl Res, 2021 Nov 15.
PMID: 34782995 DOI: 10.1007/s13346-021-01092-4

Azelaic acid (AzA) is a USFDA bioactive prescribed against acne vulgaris. It possesses delivery challenges like poor aqueous solubility, low skin-penetrability, and dose-dependent side effects, which could be overcome by its synergistic combination with tea tree oil (TTO) as a microemulsion (ME)-based hydrogel composite. AzA-TTO ME was prepared to employ pseudo-ternary phase diagram construction. The best AzA-TTO ME was of uniform size (polydispersity index 90%), and negative zeta potential (-1.42 ± 0.25% mV) values. ME hydrogel composite with optimum rheological and textural attributes showed better permeation, retention, and skin-compliant characteristics, vis-a-vis marketed formulation (Aziderm™) when evaluated in Wistar rat skin. In vitro antibacterial efficacy in bacterial strains, i.e., Staphylococcus aureus, Propionibacterium acne, and Staphylococcus epidermidis, was evaluated employing agar well plate diffusion and broth dilution assay. ME hydrogel has shown an increase in zone of inhibition by two folds and a decrease in minimum inhibitory concentration (MIC) by eightfold against P. acnes vis-a-vis AzA. Finally, ME hydrogel composite exhibited a better reduction in the papule density (93.75 ± 1.64%) in comparison to Aziderm™ 72.69 ± 4.67%) on acne as developed in rats by inducing testosterone. Thus, the developed AzA-TTO ME hydrogel composite promises an efficacious and comparatively safer drug delivery system for the topical therapy of acne vulgaris.
Perfluorocarbons Therapeutics in Modern Cancer Nanotechnology for Hypoxiainduced Anti-tumor Therapy

Satija S, Sharma P, Kaur H, Dhanjal DS, Chopra RS, Khurana N, et al.

Curr Pharm Des, 2021;27(43):4376-4387.
PMID: 34459378 DOI: 10.2174/1381612827666210830100907

With an estimated failure rate of about 90%, immunotherapies that are intended for the treatment of solid tumors have caused an anomalous rise in the mortality rate over the past decades. It is apparent that resistance towards such therapies primarily occurs due to elevated levels of HIF-1 (Hypoxia-induced factor) in tumor cells, which are caused by disrupted microcirculation and diffusion mechanisms. With the advent of nanotechnology, several innovative advances were brought to the fore; and, one such promising direction is the use of perfluorocarbon nanoparticles in the management of solid tumors. Perfluorocarbon nanoparticles enhance the response of hypoxia-based agents (HBAs) within the tumor cells and have been found to augment the entry of HBAs into the tumor micro-environment. The heightened penetration of HBAs causes chronic hypoxia, thus aiding in the process of cell quiescence. In addition, this technology has also been applied in photodynamic therapy, where oxygen self-enriched photosensitizers loaded perfluorocarbon nanoparticles are employed. The resulting processes initiate a cascade, depleting tumour oxygen and turning it into a reactive oxygen species eventually to destroy the tumour cell. This review elaborates on the multiple applications of nanotechnology based perfluorocarbon formulations that are being currently employed in the treatment of tumour hypoxia.
A Potential MRI Agent and an Anticancer Drug Encapsulated within CPMV Virus-Like Particles

Aljabali AAA, Alzoubi L, Hamzat Y, Alqudah A, Obeid MA, Al Zoubi MS, et al.

Comb Chem High Throughput Screen, 2021;24(10):1557-1571.
PMID: 32928083 DOI: 10.2174/1386207323666200914110012

BACKGROUND: Virus nanoparticles have been extensively studied over the past decades for theranostics applications. Viruses are well-characterized, naturally occurring nanoparticles that can be produced in high quantity with a high degree of similarity in both structure and composition.
OBJECTIVES: The plant virus Cowpea Mosaic Virus (CPMV) has been innovatively used as a nanoscaffold. Utilization of the internal cavity of empty Virus-Like Particles (VLPs) for the inclusion of therapeutics within the capsid has opened many opportunities in drug delivery and imaging applications.
METHODS: The encapsidation of magnetic materials and anticancer drugs was achieved. SuperscriptCPMV denotes molecules attached to the external surface of CPMV and CPMVSubscript denotes molecules within the interior of the capsid.
RESULTS: Here, the generation of novel VLPs incorporating iron-platinum nanoparticles TCPMVFePt and cisplatin (Cis) (TCPMVCis) is reported. TCPMVCis exhibited a cytotoxic IC50 of TCPMVCis on both A549 and MDA-MB-231 cell lines of 1.8 μM and 3.9 μM, respectively after 72 hours of incubation. The TCPMVFePt were prepared as potential MRI contrast agents.
CONCLUSION: Cisplatin loaded VLP (TCPMVCis) is shown to enhance cisplatin cytotoxicity in cancer cell lines with its potency increased by 2.3-folds.
Fulltext Exosomal mediated signal transduction through artificial microRNA (amiRNA): A potential target for inhibition of SARS-CoV-2

Vadivalagan C, Shitut A, Kamalakannan S, Chen RM, Serrano-Aroca Á, Mishra V, et al.

Cell Signal, 2022 Jul;95:110334.
PMID: 35461900 DOI: 10.1016/j.cellsig.2022.110334

Exosome trans-membrane signals provide cellular communication between the cells through transport and/or receiving the signal by molecule, change the functional metabolism, and stimulate and/or inhibit receptor signal complexes. COVID19 genetic transformations are varied in different geographic positions, and single nucleotide polymorphic lineages were reported in the second waves due to the fast mutational rate and adaptation. Several vaccines were developed and in treatment practice, but effective control has yet to reach in cent presence. It was initially a narrow immune-modulating protein target. Controlling these diverse viral strains may inhibit their transuding mechanisms primarily to target RNA genes responsible for COVID19 transcription. Exosomal miRNAs are the main sources of transmembrane signals, and trans-located miRNAs can directly target COVID19 mRNA transcription. This review discussed targeted viral transcription by delivering the artificial miRNA (amiRNA) mediated exosomes in the infected cells and significant resources of exosome and their efficacy.
Fulltext Self-nanoemulsifying drug delivery system (SNEDDS) mediated improved oral bioavailability of thymoquinone: optimization, characterization, pharmacokinetic, and hepatotoxicity studies

Rathore C, Hemrajani C, Sharma AK, Gupta PK, Jha NK, Aljabali AAA, et al.

Drug Deliv Transl Res, 2023 Jan;13(1):292-307.
PMID: 35831776 DOI: 10.1007/s13346-022-01193-8

Thymoquinone (TQ) is an antioxidant, anti-inflammatory, and hepatoprotective compound obtained from the black seed oil of Nigella sativa. However, high hydrophobicity, instability at higher pH levels, photosensitivity, and low oral bioavailability hinder its delivery to the target tissues. A self-nanoemulsifying drug delivery system (SNEDDS) was fabricated using the microemulsification technique to address these issues. Its physicochemical properties, thermodynamic stability studies, drug release kinetics, in vivo pharmacokinetics, and hepatoprotective activity were evaluated. The droplet size was in the nano-range (
Fulltext Alleviation of diabetic nephropathy by zinc oxide nanoparticles in streptozotocin-induced type 1 diabetes in rats

Alomari G, Al-Trad B, Hamdan S, Aljabali AAA, Al Zoubi MS, Al-Batanyeh K, et al.

IET Nanobiotechnol, 2021 Jul;15(5):473-483.
PMID: 34694755 DOI: 10.1049/nbt2.12026

This study examines the effect of nanoparticles with zinc oxides (ZnONPs) on diabetic nephropathy, which is the primary cause of mortality for diabetic patients with end-stage renal disease. Diabetes in adult male rats was induced via intraperitoneal injection of streptozotocin. ZnONPs were intraperitoneally administered to diabetic rats daily for 7 weeks. Diabetes was associated with increases in blood glucose level, 24-h urinary albumin excretion rate, glomerular basement membrane thickness, renal oxidative stress markers, and renal mRNA or protein expression of transforming growth factor-β1, fibronectin, collagen-IV, tumour necrosis factor-α and vascular endothelial growth factor-A. Moreover, the expression of nephrin and podocin, and the mRNA expression of matrix metalloproteinase-9 were decreased in the diabetic group. These changes were not detected in the control group and were significantly prevented by ZnONP treatment. These results provide evidence that ZnONPs ameliorate the renal damage induced in a diabetic rat model of nephropathy through improving renal functionality; inhibiting renal fibrosis, oxidative stress, inflammation and abnormal angiogenesis; and delaying the development of podocyte injury. The present findings may help design the clinical application of ZnONPs for protection against the development of diabetic nephropathy.
Fulltext Correction: Aljabali, A.A.A.; et al. Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer via down Regulation of Nuclear p65 and HIF-1α. Cancers 2020, 12, 113

Aljabali AAA, Bakshi HA, Hakkim FL, Haggag YA, Al-Batanyeh KM, Zoubi MSA, et al.

Cancers (Basel), 2020 Nov 30;12(12).
PMID: 33266353 DOI: 10.3390/cancers12123587

The authors wish to make the following corrections to this paper [...].
Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

Lee LY, Hew GSY, Mehta M, Shukla SD, Satija S, Khurana N, et al.

Life Sci, 2021 Feb 15;267:118973.
PMID: 33400932 DOI: 10.1016/j.lfs.2020.118973

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.
Fulltext Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage

Bakshi HA, Zoubi MSA, Hakkim FL, Aljabali AAA, Rabi FA, Hafiz AA, et al.

Nutrients, 2020 06 26;12(6).
PMID: 32604971 DOI: 10.3390/nu12061901

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.
Molecular mechanisms of action of naringenin in chronic airway diseases

Chin LH, Hon CM, Chellappan DK, Chellian J, Madheswaran T, Zeeshan F, et al.

Eur J Pharmacol, 2020 Jul 15;879:173139.
PMID: 32343971 DOI: 10.1016/j.ejphar.2020.173139

Chronic airway inflammatory diseases are characterized by persistent proinflammatory responses in the respiratory tract. Although, several treatment strategies are currently available, lifelong therapy is necessary for most of these diseases. In recent years, phytophenols, namely, flavonoids, derived from fruits and vegetables have been gaining tremendous interest and have been extensively studied due to their low toxicological profile. Naringenin is a bioflavonoid abundantly found in citrus fruits. This substance has shown notable therapeutic potential in various diseases due to its promising diverse biological activities. In this review, we have attempted to review the published studies from the available literature, discussing the molecular level mechanisms of naringenin in different experimental models of airway inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis and cystic fibrosis. Current evidences have proposed that the anti-inflammatory properties of naringenin play a major role in ameliorating inflammatory disease states. In addition, naringenin also possesses several other biological properties. Despite the proposed mechanisms suggesting remarkable therapeutic benefits, the clinical use of naringenin is, however, hampered by its low solubility and bioavailability. Furthermore, this review also discusses on the studies that utilise nanocarriers as a drug delivery system to address the issue of poor solubility.
Fulltext An overview of vaccine development for COVID-19

Shahcheraghi SH, Ayatollahi J, Aljabali AA, Shastri MD, Shukla SD, Chellappan DK, et al.

Ther Deliv, 2021 03;12(3):235-244.
PMID: 33624533 DOI: 10.4155/tde-2020-0129

The COVID-19 pandemic continues to endanger world health and the economy. The causative SARS-CoV-2 coronavirus has a unique replication system. The end point of the COVID-19 pandemic is either herd immunity or widespread availability of an effective vaccine. Multiple candidate vaccines - peptide, virus-like particle, viral vectors (replicating and nonreplicating), nucleic acids (DNA or RNA), live attenuated virus, recombinant designed proteins and inactivated virus - are presently under various stages of expansion, and a small number of vaccine candidates have progressed into clinical phases. At the time of writing, three major pharmaceutical companies, namely Pfizer and Moderna, have their vaccines under mass production and administered to the public. This review aims to investigate the most critical vaccines developed for COVID-19 to date.
Overview of key molecular and pharmacological targets for diabetes and associated diseases

Shahcheraghi SH, Aljabali AAA, Al Zoubi MS, Mishra V, Charbe NB, Haggag YA, et al.

Life Sci, 2021 Aug 01;278:119632.
PMID: 34019900 DOI: 10.1016/j.lfs.2021.119632

Diabetes epidemiological quantities are demonstrating one of the most important communities' health worries. The essential diabetic difficulties are including cardiomyopathy, nephropathy, inflammation, and retinopathy. Despite developments in glucose decreasing treatments and drugs, these diabetic complications are still ineffectively reversed or prohibited. Several signaling and molecular pathways are vital targets in the new therapies of diabetes. This review assesses the newest researches about the key molecules and signaling pathways as targets of molecular pharmacology in diabetes and diseases related to it for better treatment based on molecular sciences. The disease is not cured by current pharmacological strategies for type 2 diabetes. While several drug combinations are accessible that can efficiently modulate glycemia and mitigate long-term complications, these agents do not reverse pathogenesis, and in practice, they are not established to modify the patient's specific molecular profiling. Therapeutic companies have benefited from human genetics. Genome exploration, which is agnostic to the information that exists, has revealed tens of loci that impact glycemic modulation. The physiological report has begun to examine subtypes of diseases, illustrate heterogeneity and propose biochemical therapeutic pathways.
Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

Chellappan DK, Yee LW, Xuan KY, Kunalan K, Rou LC, Jean LS, et al.

Drug Dev Res, 2020 06;81(4):419-436.
PMID: 32048757 DOI: 10.1002/ddr.21648

Neutrophils are essential effector cells of immune system for clearing the extracellular pathogens during inflammation and immune reactions. Neutrophils play a major role in chronic respiratory diseases. In respiratory diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer and others, there occurs extreme infiltration and activation of neutrophils followed by a cascade of events like oxidative stress and dysregulated cellular proteins that eventually result in apoptosis and tissue damage. Dysregulation of neutrophil effector functions including delayed neutropil apoptosis, increased neutrophil extracellular traps in the pathogenesis of asthma, and chronic obstructive pulmonary disease enable neutrophils as a potential therapeutic target. Accounting to their role in pathogenesis, neutrophils present as an excellent therapeutic target for the treatment of chronic respiratory diseases. This review highlights the current status and the emerging trends in novel drug delivery systems such as nanoparticles, liposomes, microspheres, and other newer nanosystems that can target neutrophils and their molecular pathways, in the airways against infections, inflammation, and cancer. These drug delivery systems are promising in providing sustained drug delivery, reduced therapeutic dose, improved patient compliance, and reduced drug toxicity. In addition, the review also discusses emerging strategies and the future perspectives in neutrophil-based therapy.
Fulltext Targeting LIN28: a new hope in prostate cancer theranostics

Shrivastava G, Aljabali AA, Shahcheraghi SH, Lotfi M, Shastri MD, Shukla SD, et al.

Future Oncol, 2021 Oct;17(29):3873-3880.
PMID: 34263659 DOI: 10.2217/fon-2021-0247

The mortality and morbidity rates for prostate cancer have recently increased to alarming levels, rising higher than lung cancer. Due to a lack of drug targets and molecular probes, existing theranostic techniques are limited. Human LIN28A and its paralog LIN28B overexpression are associated with a number of tumors resulting in a remarkable increase in cancer aggression and poor prognoses. The current review aims to highlight recent work identifying the key roles of LIN28A and LIN28B in prostate cancer, and to instigate further preclinical and clinical research in this important area.
Fulltext The viral capsid as novel nanomaterials for drug delivery

Aljabali AA, Hassan SS, Pabari RM, Shahcheraghi SH, Mishra V, Charbe NB, et al.

Future Sci OA, 2021 Oct;7(9):FSO744.
PMID: 34737885 DOI: 10.2144/fsoa-2021-0031

The purpose of this review is to highlight recent scientific developments and provide an overview of virus self-assembly and viral particle dynamics. Viruses are organized supramolecular structures with distinct yet related features and functions. Plant viruses are extensively used in biotechnology, and virus-like particulate matter is generated by genetic modification. Both provide a material-based means for selective distribution and delivery of drug molecules. Through surface engineering of their capsids, virus-derived nanomaterials facilitate various potential applications for selective drug delivery. Viruses have significant implications in chemotherapy, gene transfer, vaccine production, immunotherapy and molecular imaging.

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